New Oral Anticoagulants: A Review

Babak Moini, MDVeterans Affairs Hospital

Noon Lecture Series

Acknowledgment:Some of the slides were borrowed from Amanda

Miller Phar.D.

Case168 male with hx of DM, CHF and prior ischemic

CVA admitted for new afib. He has a hx of non-compliance.

CHADs2: 4.

Which anticoagulant to send him home with?

Oral Anticoagulants Available in US

Coumadin

warfarin

1954

Pradaxa®

dabigatran

2010

Xarelto®rivaroxab

an

2011

Eliquis®apixaban

2012

Mechanism of ActionMedication Mechanism of Action

Coumadin (warfarin)

Vitamin K Antagonist

Pradaxa (dabigatran)

Direct Thrombin Inhibitor

Xarelto (rivaroxaban)

Factor Xa Inhibitor

Eliquis (apixaban)

Factor Xa Inhibitor

http://www.healio.com/~/media/Images/News/Online/Orthopedics/2009/12_December/01/79_fig_400_307_57368.gif

rivaroxabanapixaban

dabigatran

Pharmacology:Coumadin Dabigatran Rivaroxaba

nApixaban

Bioavailability

100% 3-7% 60-100% 50%

Protein bound

99% 30% 90-95% 80-85%

Metabolism CYP Conjugation CYP CYP

Half Life 40hrs 12-17hrs 5-9hrs 12hrs

Onset of action

72hrs 1-2hrs 2-4hrs 2-4hrs

Elimination Liver Renal Renal Renal

Indications: USCoumadin Dabigatrn Rivaroxaba

nApixaban

Afib + + (RELY) + (ROCKET-AF)

+ (Aristotle)+ (AVERROES)

DVT/PE + Not yet. (RECOVER) +

(EINSTEIN)

Post TKA/THADVT prophylaxis

+ + + (RECORD 1-3)

+ (ADVANCE)

Not yet approved: Rivaroxaban for prophylaxis of DVT in medically ill patients (MAGELLAN). Rivaroxaban vs Enoxaparin. NI < 30 days, superior at 35 days.

Usual Dosing (A fib)

•Once daily, titrate to INR 2-3Warfarin•150 mg BID •75 mg BID (CrCl 15-30 ml/min) Dabigatran

•20 mg daily•15 mg daily (CrCl 15-50 ml/min) Rivaroxaban

• 5 mg BID• 2.5 mg BID if any 2 of the

following: age > 80, wt < 60kg, SCr > 1.5

Apixaban

Usual Dosing (VTE)Only FDA-approved agent = rivaroxaban

VTE Prophylaxis (knee/hip surgery) 10mg once daily (up to 35 days) No renal dose (CrCl < 30 ml/min avoid)

VTE Treatment: 15 mg BID x 3 weeks then 20mg daily No renal dose (CrCl < 30 ml/min avoid)

Perioperative Recommendations

• Hold 1-2 days before procedure • CrCl < 50 hold 3-5 days

Dabigatran

• Low bleed risk hold 1 day• CrCl < 30/ low risk hold 2 days• High bleed risk hold 2 days• CrCl < 30/ high risk hold 4 days

Rivaroxaban

• Low bleed risk hold x 1 day • High bleed risk hold x 2 days

Apixaban

Dabigatran PI, Blood 2012;119:3016-23

Major Side Effects:Bleeding: varied definition in each study.

GI ICHMajor (drop in Hgb by 2, life threatening).

Dabigatran: Pills are made in acidic content, hence has 20%

rate of GI side effects. ? Observed increase risk of GI bleeding.

Monitoring Levels:Coumadin: INR

New Oral anticoagulants: no standardized studies. No accurate quantitative measures.

Dabigatran: ECT, Thrombin clotting timeRivaroxaban: special anti-Xa activityAbixaban special anti-Xa activity

Drug-Drug Interactions:No where as severe as with Warfarin.

Dabigatran: P-glycoprotein, pro-drug.Needs acidic environment, avoid co-administration

with PPI.

Rivaroxaban: CYP-450 and P-glycoprotein. Caution with dual inhibitors (Ketoconazole,

Itroconazole, Clarithromycin). No dose adjustments needed.

Abixaban: CYP3A4 and P-glycoprotein.Decrease dose to 2.5mg bid in dual inhibitors.

Switching To/From Warfarin

Medication Recommendations for Conversion

DabigatranStop warfarin, initiate dabigatran when INR < 2

Initiate warfarin 3 days before D/C dabigatran

Rivaroxaban

Stop warfarin, initiate rivaroxaban when INR < 2-3

Initiate warfarin with bridging 24 hours after D/C rivaroxaban

Apixaban

Stop warfarin, initiate apixaban when INR < 2

Initiate warfarin with bridging when next apixaban dose is due.

Gonsalves Et al. Mayo Clinic Proc. 5-2013

Treatment of Bleeding:No evidence based guidelines.

Remember that unlike Coumadin, the new OAC will continuously bind to factor Xa or thrombin, hence making FFP less useful.

Current available Rx for life threatening active bleeding: based on case reports. Factor VII PCC: 3 and 4 factor concentrates. HD: only for Dabigatran. Large volume of distribution. Charcoal

Trials vs Warfarin for A Fib RE-LY

DAB vs WARROCKET-AFRIV vs WAR

ARISTOTLEAPIX vs WAR

Comparator Dabigatran Rivaroxaban Apixaban

Design Open-label, blind outcomes, noninferiority

Double-blind, noninferiority

Double-blind, noninferiority

Sample size n = 18,113 n = 14,264 n = 18,201

Randomization D 150mg BIDD 110mg BID

W (INR 2-3)

R 20mg daily* W (INR 2-3)

A 5mg BID* W (INR 2-3)

InclusionCriteria Nonvalvular AF

with increased stroke risk

Nonvalvular AF with prior

stroke or >2 risk factors

Nonvalvular AF with >1 risk

factor for stroke

Exclusion CrCl < 30 CrCl < 30 CrCl < 25

* Dose reductions for renal impairment

Trials vs Warfarin for A fibRE-LY

DAB vs WARROCKET-AFRIV vs WAR

ARISTOTLE APIX vs WAR

Average age (yrs) 71 73 70

Mean CHADS2 2.1 3.5 2.1

0-1 32% 0% 34%

2 36% 13% 36%

3-6 32% 87% 30%

Prior TIA/stroke 20% 55% 19%

TTR (INR @ goal) 64% 55% 62%

Median follow-up 2 yrs 1.9 yrs 1.8 yrs

Primary endpoint Stroke (ischemic, hemorrhagic) + systemic embolism

Major Findings:RELY

Dabigatran 110mg NI to Warfarin (1.53% vs 1.69%). Dabigatran 150mg superior to Warfarin ONLY if

compared with sub-optimal INR subgroup (1.11 % vs 1.69%).

Major bleeding less with 110mg (2.71 vs 3.11%).

ROCKET-AFRivaroxaban NI to Warfarin (2.1% vs 2.4%)Less ICH or fatal bleeding (0.4% vs 0.8% )

ARISTOTLE:Abixaban Superior to Warfarin (1.27% vs 1.6% )Less Major bleeding (1.4% vs 2.1% )

Key Safety Endpoints (% per year) RE-LY ROCKET AF ARISTOTLE

D110 D150 WAR RIV WAR APIX WAR

1o bleeding endpoint* 2.71 3.11 3.36 14.9 14.5 2.13 3.09

Major bleed 2.71 3.11 3.36 5.55 5.42 2.13 3.09

GI bleeding 1.12 1.51 1.02 3.2 2.2 0.76 0.86

Intracranial hemorrhage

0.23 0.3 0.74 0.5 0.7 0.33 0.8

*: Primary safety endpoint:o RE-LY major hemorrhage o ROCKET-AF major + non-major clinically relevant bleeding o ARISTOTLE ISTH (Int Soc Thromosis & Hemostasis) major bleeding

Figure 3 Forest plot for (A) major bleeding, (B) intracranial bleeding, and (C) gastrointestinal bleeding, new oral anticoagulants (NOA) versus warfarin in patients with AF.

http://dx.doi.org/10.1016/j.amjcard.2012.03.049

Quick Review of Evidence- Based Medicine:

I A: Systemic review of multiple RCTs / multiple RTCs B: High quality single RTC

II: A: Systemic review of cohort studies B: High quality cohort studie(s)

III: Systemic review of Case/Control studies / Case Control studies

IV Case reports

IV Expert opinion

Anticoagulation Recommendations (AF) Risk/CHADS2 CHEST 2012 AHA/ASA

Low RiskCHADS2 = 0

No therapy > antithrombotic therapy (2B)

Aspirin (75-325mg) > OAC (2B) or aspirin + clopidogrel (2B)

Aspirin (1A)

Intermediate CHADS2 = 1

OAC > no therapy (1B)

OAC > aspirin (2B) or aspirin + clopidogrel (2B)

OAC unsuitable or pt refuses: aspirin + clopidogrel over aspirin monotherapy (2B)

Warfarin (1A)

Aspirin, if patient preference (1A)

High RiskCHADS2 > 2

OAC > no therapy (1A)

OAC > aspirin (1B) or aspirin + clopidogrel (1B)

OAC unsuitable or pt refuses: aspirin + clopidogrel over aspirin monotherapy (1B)

Dabigatran 150mg BID > warfarin (2B)

Warfarin (1A)Dabigatran (1B)Rivaroxaban (2A)Apixaban (1B)

OAC = oral anticoagulation

Chest 2012; 141:e531S-e575SStroke 2012;43: 3442-3453

New OAC: Pros:

Easy administration Immediate effect Much less food and drug

interactions One dose fits all The names sound so

much cooler than WARFARIN.

Cons: Expensive Inability to monitor

compliance Short duration: loss of

effect with a single missed dose

No safe/reliable antidotes ? Bleeding. Observational

bias vs real difference. Renal dosing

Take home message:Coumadin still remains the drug of choice for many

patients due to cost, past experience and known side effects.

Many new OAC are in the pipeline, expect a barrage of pharma bombardments, must remain objective as many of the studies have different inclusion/exclusion criteria, definition of end points and side effects.

Each patient may benefit from a different type of OAC based on comorbidities and drug side effect profile.

Watch out for recall bias with the new OAC among your own colleagues.

Patient compliance is a major factor: remember with the new OAC one missed dose means a lot!

The End!